Melatonin impedes NCOA4/ACSL4-dependent ferroptosis by targeting STING to ameliorate diabetic cognitive dysfunction

Melatonin (MLT) is a potentially effective therapeutic agent for mitigating brain injury under various pathological conditions. However, the molecular mechanisms of its ability to ameliorate diabetic cognitive dysfunction (DCD) require further elucidation. In this study, we demonstrated that MLT administration improved the learning and memory deficits in type 2 diabetes mellitus (T2DM) mice, concurrently attenuated acyl-CoA synthetase long-chain family member 4 (ACSL4) - dependent ferroptosis in diabetic brain tissue and neuronal cells exposed to high glucose/palmitic acid (HG + PA), as indicated by reduced lipid peroxidation, elevated GSH and SOD levels, increased GPX4 levels, and downregulated ACSL4 expression. Furthermore, MLT reversed nuclear receptor coactivator 4 (NCOA4) -mediated ferritinophagy in vivo and in vitro. This opinion was demonstrated by decreased intracellular ROS and Fe²⁺ levels, reduced NCOA4 expression, and increased Ferritin levels. Mechanistic investigations revealed that MLT directly binds to stimulator of interferon genes (STING) and suppresses its expression and activation, as determined by surface plasmon resonance, molecular docking, and cellular thermal shift assays. Consequently, MLT treatment disrupted the subsequent recruitment of NCOA4 and ACSL4 to STING. Pharmacological activation or genetic overexpression of STING attenuated the inhibitory effect of MLT on ferroptosis and ferritinophagy. In contrast, STING silencing had the opposite effects under the aforementioned conditions. Our findings revealed that melatonin exerts dual regulatory mechanisms, inhibiting ACSL4-dependent ferroptosis and suppressing NCOA4 axis-mediated ferritinophagy through directly targeting STING, thereby ameliorating diabetic cognitive dysfunction.